Sensory neurons promote immune homeostasis in the lung.

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPß was dependent on JAK1 in the vagus nerve, and CGRPß suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.

Sensory Neurons that Detect Stretch and Nutrients in the Digestive System.

Neural inputs from internal organs are essential for normal autonomic function. The vagus nerve is a key body-brain connection that monitors the digestive, cardiovascular, and respiratory systems. Within the gastrointestinal tract, vagal sensory neurons detect gut hormones and organ distension. Here, we investigate the molecular diversity of vagal sensory neurons and their roles in sensing gastrointestinal inputs. Genetic approaches allowed targeted investigation of gut-to-brain afferents involved in homeostatic responses to ingested nutrients (GPR65 neurons) and mechanical distension of the stomach and intestine (GLP1R neurons). Optogenetics, in vivo ganglion imaging, and genetically guided anatomical mapping provide direct links between neuron identity, peripheral anatomy, central anatomy, conduction velocity, response properties in vitro and in vivo, and physiological function. These studies clarify the roles of vagal afferents in mediating particular gut hormone responses. Moreover, genetic control over gut-to-brain neurons provides a molecular framework for understanding neural control of gastrointestinal physiology.

Vagal Sensory Neuron Subtypes that Differentially Control Breathing.

Breathing is essential for survival and under precise neural control. The vagus nerve is a major conduit between lung and brain required for normal respiration. Here, we identify two populations of mouse vagus nerve afferents (P2ry1, Npy2r), each a few hundred neurons, that exert powerful and opposing effects on breathing. Genetically guided anatomical mapping revealed that these neurons densely innervate the lung and send long-range projections to different brainstem targets. Npy2r neurons are largely slow-conducting C fibers, while P2ry1 neurons are largely fast-conducting A fibers that contact pulmonary endocrine cells (neuroepithelial bodies). Optogenetic stimulation of P2ry1 neurons acutely silences respiration, trapping animals in exhalation, while stimulating Npy2r neurons causes rapid, shallow breathing. Activating P2ry1 neurons did not impact heart rate or gastric pressure, other autonomic functions under vagal control. Thus, the vagus nerve contains intermingled sensory neurons constituting genetically definable labeled lines with different anatomical connections and physiological roles.

A multidimensional coding architecture of the vagal interoceptive system.

Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival1-4. Vagal sensory neurons (VSNs) form an important body-to-brain connection, navigating visceral organs along the rostral-caudal axis of the body and crossing the surface-lumen axis of organs into appropriate tissue layers5,6. The brain can discriminate numerous body signals through VSNs, but the underlying coding strategy remains poorly understood. Here we show that VSNs code visceral organ, tissue layer and stimulus modality-three key features of an interoceptive signal-in different dimensions. Large-scale single-cell profiling of VSNs from seven major organs in mice using multiplexed projection barcodes reveals a 'visceral organ' dimension composed of differentially expressed gene modules that code organs along the body's rostral-caudal axis. We discover another 'tissue layer' dimension with gene modules that code the locations of VSN endings along the surface-lumen axis of organs. Using calcium-imaging-guided spatial transcriptomics, we show that VSNs are organized into functional units to sense similar stimuli across organs and tissue layers; this constitutes a third 'stimulus modality' dimension. The three independent feature-coding dimensions together specify many parallel VSN pathways in a combinatorial manner and facilitate the complex projection of VSNs in the brainstem. Our study highlights a multidimensional coding architecture of the mammalian vagal interoceptive system for effective signal communication.

The Coding Logic of Interoception.

Interoception, the ability to precisely and timely sense internal body signals, is critical for life. The interoceptive system monitors a large variety of mechanical, chemical, hormonal, and pathological cues using specialized organ cells, organ innervating neurons, and brain sensory neurons. It is important for maintaining body homeostasis, providing motivational drives, and regulating autonomic, cognitive, and behavioral functions. However, compared to external sensory systems, our knowledge about how diverse body signals are coded at a system level is quite limited. In this review, we focus on the unique features of interoceptive signals and the organization of the interoceptive system, with the goal of better understanding the coding logic of interoception.

Non-KREEP origin for Chang'e-5 basalts in the Procellarum KREEP Terrane.

Mare volcanics on the Moon are the key record of thermo-chemical evolution throughout most of lunar history1-3. Young mare basalts-mainly distributed in a region rich in potassium, rare-earth elements and phosphorus (KREEP) in Oceanus Procellarum, called the Procellarum KREEP Terrane (PKT)4-were thought to be formed from KREEP-rich sources at depth5-7. However, this hypothesis has not been tested with young basalts from the PKT. Here we present a petrological and geochemical study of the basalt clasts from the PKT returned by the Chang'e-5 mission8. These two-billion-year-old basalts are the youngest lunar samples reported so far9. Bulk rock compositions have moderate titanium and high iron contents  with KREEP-like rare-earth-element and high thorium concentrations. However, strontium-neodymium isotopes indicate that these basalts were derived from a non-KREEP mantle source. To produce the high abundances of rare-earth elements and thorium, low-degree partial melting and extensive fractional crystallization are required. Our results indicate that the KREEP association may not be a prerequisite for young mare volcanism. Absolving the need to invoke heat-producing elements in their source implies a more sustained cooling history of the lunar interior to generate the Moon's youngest melts.

The vagus nerve in cardiovascular physiology and pathophysiology: From evolutionary insights to clinical medicine.

The parasympathetic nervous system via the vagus nerve exerts profound influence over the heart. Together with the sympathetic nervous system, the parasympathetic nervous system is responsible for fine-tuned regulation of all aspects of cardiovascular function, including heart rate, rhythm, contractility, and blood pressure. In this review, we highlight vagal efferent and afferent innervation of the heart, with a focus on insights from comparative biology and advances in understanding the molecular and genetic diversity of vagal neurons, as well as interoception, parasympathetic dysfunction in heart disease, and the therapeutic potential of targeting the parasympathetic nervous system in cardiovascular disease.

Peptide Self-assembly: From Ordered to Disordered.

Biomolecular self-assembly is a ubiquitous occurrence in nature that gives rise to sophisticated superstructures that enable the implementation of complex biological functions. It encompasses both ordered structures, such as the DNA double helix, and disordered structures, such as the nucleolus and other nonmembranous organelles. In contrast to these highly organized ordered structures, which exhibit specific patterns or symmetry, disordered structures are characterized by their flexible and randomized molecular organization, which provides versatility, dynamicity, and adaptability to biological systems and contributes to the complexity and functionality of living organisms. However, these disordered structures usually exist in a thermodynamically metastable state. This means that these disordered structures are unstable and difficult to observe due to their short existence time. Achieving disordered structures through precise control of the assembly process and ensuring their stability and integrity pose significant challenges. Currently, ongoing research efforts are focused on the self-assembly of proteins with intrinsically disordered regions (IDRs). However, the structural complexity and instability of proteins present prohibitive difficulties in elucidating the multiscale self-assembly process. Therefore, simple peptides, as a segment of proteins, hold great promise in constructing self-assembly systems for related research. Since our finding on droplet-like disordered structures that occur transiently during the peptide self-assembly (PSA), our research is centered around the dynamic evolution of peptide supramolecular systems, particularly the modulation of a variety of assembled structures ranging from ordered to disordered.In this Account, we narrate our recent research endeavors on supramolecular structures formed by PSA, spanning from ordered structures to disordered structures. We delve into the mechanisms of structural regulation, shedding light on how these peptide-based structures can be controlled more precisely. Moreover, we emphasize the functional applications that arise from these structures. To begin, we conduct a comprehensive overview of various types of ordered structures that emerge from PSA, showcasing their diverse applications. Following, we elaborate on the discovery and development of droplet-like disordered structures that arise during PSA. A mechanistic study on multistep self-assembly processes mediated by liquid-liquid phase separation (LLPS) is critically emphasized. Ordered structures with different morphologies and functions can be obtained by subtly controlling and adjusting the metastable liquid droplets. In particular, we have recently developed solid glasses with long-range disorder, including noncovalent biomolecular glass based on amino acid and peptide derivatives, as well as high-entropy glass based on cyclic peptides. This demonstrates the great potential of using biologically derived molecules to create green and sustainable glassy materials.

Cardiovascular Brain Circuits.

The cardiovascular system is hardwired to the brain via multilayered afferent and efferent polysynaptic axonal connections. Two major anatomically and functionally distinct though closely interacting subcircuits within the cardiovascular system have recently been defined: The artery-brain circuit and the heart-brain circuit. However, how the nervous system impacts cardiovascular disease progression remains poorly understood. Here, we review recent findings on the anatomy, structures, and inner workings of the lesser-known artery-brain circuit and the better-established heart-brain circuit. We explore the evidence that signals from arteries or the heart form a systemic and finely tuned cardiovascular brain circuit: afferent inputs originating in the arterial tree or the heart are conveyed to distinct sensory neurons in the brain. There, primary integration centers act as hubs that receive and integrate artery-brain circuit-derived and heart-brain circuit-derived signals and process them together with axonal connections and humoral cues from distant brain regions. To conclude the cardiovascular brain circuit, integration centers transmit the constantly modified signals to efferent neurons which transfer them back to the cardiovascular system. Importantly, primary integration centers are wired to and receive information from secondary brain centers that control a wide variety of brain traits encoded in engrams including immune memory, stress-regulating hormone release, pain, reward, emotions, and even motivated types of behavior. Finally, we explore the important possibility that brain effector neurons in the cardiovascular brain circuit network connect efferent signals to other peripheral organs including the immune system, the gut, the liver, and adipose tissue. The enormous recent progress vis-à-vis the cardiovascular brain circuit allows us to propose a novel neurobiology-centered cardiovascular disease hypothesis that we term the neuroimmune cardiovascular circuit hypothesis.

Distinct transcriptional alterations distinguish Lewy body disease from Alzheimer's disease.

Lewy body dementia and Alzheimer's disease (AD) are leading causes of cognitive impairment, characterized by distinct but overlapping neuropathological hallmarks. Lewy body disease (LBD) is characterized by alpha-synuclein aggregates in the form of Lewy bodies as well as the deposition of extracellular amyloid plaques, with many cases also exhibiting neurofibrillary tangle (NFT) pathology. In contrast, Alzheimer's disease is characterized by amyloid plaques and neurofibrillary tangles. Both conditions often co-occur with additional neuropathological changes, such as vascular disease and TDP-43 pathology. To elucidate shared and distinct molecular signatures underlying these mixed neuropathologies, we extensively analyzed transcriptional changes in the anterior cingulate cortex, a brain region critically involved in cognitive processes. We performed bulk tissue RNAseq from the anterior cingulate cortex and determined differentially expressed genes (q-value < 0.05) in control (n = 81), Lewy body disease (n = 436), Alzheimer's disease (n = 53), and pathological amyloid cases consisting of amyloid pathology with minimal or no tau pathology (n = 39). We used gene set enrichment and weighted gene correlation network analysis (WGCNA) to understand the pathways associated with each neuropathologically defined group. Lewy body disease cases had strong up-regulation of inflammatory pathways and down-regulation of metabolic pathways. The Lewy body disease cases were further subdivided into either high Thal amyloid, Braak NFT, or low pathological burden cohorts. Compared to the control cases, the Lewy body disease cohorts consistently showed up-regulation for genes involved in protein folding and cytokine immune response, as well as down-regulation of fatty acid metabolism. Surprisingly, concomitant tau pathology within the Lewy body disease cases resulted in no additional changes. Some core inflammatory pathways were shared between Alzheimer's disease and Lewy body disease but with numerous disease-specific changes. Direct comparison of Lewy body disease cohorts versus Alzheimer's disease cases revealed strong enrichment of synaptic signaling, behavior, and neuronal system pathways. Females had a stronger response overall in both Lewy body and Alzheimer's disease, with several sex-specific changes. Overall, the results identify genes commonly and uniquely dysregulated in neuropathologically defined Lewy body disease and Alzheimer's disease cases, shedding light on shared and distinct molecular pathways. Additionally, the study underscores the importance of considering sex-specific changes in understanding the complex transcriptional landscape of these neurodegenerative diseases.

Molecular and cellular neurocardiology in heart disease.

This paper updates and builds on a previous White Paper in this journal that some of us contributed to concerning the molecular and cellular basis of cardiac neurobiology of heart disease. Here we focus on recent findings that underpin cardiac autonomic development, novel intracellular pathways and neuroplasticity. Throughout we highlight unanswered questions and areas of controversy. Whilst some neurochemical pathways are already demonstrating prognostic viability in patients with heart failure, we also discuss the opportunity to better understand sympathetic impairment by using patient specific stem cells that provides pathophysiological contextualization to study 'disease in a dish'. Novel imaging techniques and spatial transcriptomics are also facilitating a road map for target discovery of molecular pathways that may form a therapeutic opportunity to treat cardiac dysautonomia.

Single-Electron Oxidation-Initiated Enantioselective Hydrosulfonylation of Olefins Enabled by Photoenzymatic Catalysis.

Controlling the enantioselectivity of hydrogen atom transfer (HAT) reactions has been a long-standing synthetic challenge. While recent advances on photoenzymatic catalysis have demonstrated the great potential of non-natural photoenzymes, all of the transformations are initiated by single-electron reduction of the substrate, with only one notable exception. Herein, we report an oxidation-initiated photoenzymatic enantioselective hydrosulfonylation of olefins using a novel mutant of gluconobacter ene-reductase (GluER-W100F-W342F). Compared to known photoenzymatic systems, our approach does not rely on the formation of an electron donor-acceptor complex between the substrates and enzyme cofactor and simplifies the reaction system by obviating the addition of a cofactor regeneration mixture. More importantly, the GluER variant exhibits high reactivity and enantioselectivity and a broad substrate scope. Mechanistic studies support the proposed oxidation-initiated mechanism and reveal that a tyrosine-mediated HAT process is involved.

Elk1 enhances inflammatory cell infiltration and exacerbates acute lung injury/acute respiratory distress syndrome by suppressing Fcgr2b transcription.

OBJECTIVE: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with significant mortality rates. The role of Fcgr2b in the pathogenesis of ALI/ARDS is not fully elucidated. This study aimed to investigate the functions of Fcgr2b in ALI/ARDS and explore its underlying mechanisms. METHODS: Methods: In this study, rat models of ARDS and pulmonary microvascular endothelial cell (PMVEC) injury models were established through the administration of lipopolysaccharide (LPS). The expression levels of Fcgr2b and Elk1 were quantified in both LPS-induced ARDS rats and PMVECs. Subsequent gain- and loss-of-function experiments were conducted, followed by comprehensive assessments of lung tissue for pathomorphological changes, edema, glycogen storage, fibrosis, and infiltration of inflammatory cells. Additionally, bronchoalveolar lavage fluid was analyzed for T-helper 17 (Th17) cell infiltration, inflammatory response, and microvascular permeability to evaluate lung injury severity in ARDS models. Furthermore, the activity, cytotoxicity, apoptosis, and angiogenic potential of PMVECs were assessed to gauge cell injury. The interaction between Elk1 and Fcgr2b was also examined to confirm their regulatory relationship. RESULTS: In the context of LPS-induced ARDS and PMVEC injury, Fcgr2b expression was markedly reduced, whereas Elk1 expression was elevated. Overexpression of Fcgr2b led to a decrease in Th17 cell infiltration and mitigated lung tissue damage in ARDS models, in addition to reducing LPS-induced injury in PMVECs. Elk1 was found to suppress Fcgr2b transcription through the recruitment of histone 3 lysine 9 trimethylation (H3K9me3). Knockdown of Elk1 diminished Th17 cell infiltration and lung tissue damage in ARDS models, and alleviated LPS-induced injury in PMVECs, effects that were reversed upon Fcgr2b upregulation. CONCLUSION: Elk1 negatively regulates Fcgr2b transcription, thereby augmenting the inflammatory response and exacerbating lung injury in LPS-induced ALI/ARDS.

In Situ, Rapid Synthesis of Carbon-Loaded High Density and Ultrasmall High Entropy Oxide Nanoparticles as Efficient Electrocatalysts.

High entropy materials offer almost unlimited catalytic possibilities due to their variable composition, unique structure, and excellent electrocatalytic performance. However, due to the strong tendency of nanoparticles to coarsen and agglomerate, it is still a challenge to synthesize nanoparticles using simple methods to precisely control the morphology and size of the nanoparticles in large quantities, and their large-scale application is limited by high costs and low yields. Herein, a series of high-entropy oxides (HEOs) nanoparticles with high-density and ultrasmall size (<5 nm) loaded on carbon nanosheets with large quantities are prepared by Joule-heating treatment of gel precursors in a short period of time (≈60 s). Among them, the prepared (FeCoNiRuMn)3O4-x catalyst shows the best electrocatalytic activity for oxygen evolution reaction, with low overpotentials (230 mV @10 mA cm-2, 270 mV @100 mA cm-2), small Tafel slope (39.4 mV dec-1), and excellent stability without significant decay at 100 mA cm-2 after 100 h. The excellent performance of (FeCoNiRuMn)3O4-x can be attributed to the synergistic effect of multiple elements and the inherent structural stability of high entropy systems. This study provides a more comprehensive design idea for the preparation of efficient and stable high entropy catalysts.

Accumulation of γδT cells in the decidua is promoted by RANKL which upregulates ICAM-1 via NF-κB.

In brief: The mechanism underlying the accumulation of γδT cells in the decidua, which helps maintain maternal-fetal immunotolerance in early pregnancy, is unknown. This study reveals that DSC-derived RANKL upregulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua. Abstract: Decidual γδT (dγδT) cells help maintain maternal-fetal immunotolerance in early pregnancy. However, the mechanism underlying the accumulation of γδT cells in the decidua is unknown. Previous work showed that RANKL upregulated intercellular adhesion molecule 1 (ICAM-1) in decidual stromal cells (DSCs), and Rankl knockout mice had limited dγδT cell populations. In this study, we measured the expression levels of RANKL/RANK and ICAM-1 in DSCs, in addition to the integrins of ICAM-1 on dγδT cells, and the number of dγδT cells from patients with recurrent spontaneous abortion (RSA) and normal pregnant women in the first trimester. RSA patients showed significantly decreased RANKL/RANK and ICAM-1/CD11a signaling in decidua, and a decreased percentage of dγδT cells, which was positively correlated with DSC-derived RANKL and ICAM-1. Next, an in vitro adhesion experiment showed that the enhanced attraction of human DSCs to dγδT cells after RANKL overexpression was almost completely aborted by anti-ICAM-1. Furthermore, Rankl knockout mice showed a significant reduction in NF-κB activity compared with wild-type controls. Finally, we applied a selective NF-κB inhibitor named PDTC to validate the role of NF-κB in RANKL-mediated ICAM-1 upregulation. Taken together, our data show that DSC-derived RANKL upregulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua. A reduction in RANKL/ICAM-1 signaling in DSCs may result in insufficient accumulation of γδT cells in decidua and, in turn, RSA.

Roles of caregiver-child interaction on the association of socioeconomic status with early childhood development: a population-based study in rural China.

OBJECTIVE: Socioeconomic status (SES) has been previously associated with children's early development, health, and nutrition; however, evidence about the potential role of caregiver-child interaction in such associations was limited. This study aimed to explore the effect of caregiver-child interaction on the associations of SES with child developmental outcomes, including early neurodevelopment and social-emotional behavior. METHODS: A cross-sectional survey was conducted among 2078 children aged 0-6 in a rural county that just lifted out of poverty in 2020 in Central China. The Ages & Stages Questionnaires-Chinese version (ASQ-C) and the Social-Emotional (ASQ: SE) questionnaire were used to assess children's early neurodevelopment and social-emotional behavior, respectively. Caregiver-child interaction was evaluated with the Brigance Parent-Child Interactions Scale. Regression-based statistical mediation and moderation effect were conducted with the PROCESS macro of SPSS. RESULTS: Children with low SES had an increased risk of suspected neurodevelopmental delay [OR = 1.92, 95% CI: 1.50, 2.44] and social-emotional developmental delay [OR = 1.31, 95% CI: 1.04, 1.66]. The caregiver-child interaction partially mediated the associations of SES with child developmental outcomes; the proportion of the indirect effect was 14.9% for ASQ-C total score and 32.1% for ASQ: SE score. Moreover, the caregiver-child interaction had a significant moderation effect on the association of SES with ASQ-C total score (P < 0.05). A weaker association was observed in children with high-level caregiver-child interaction than in medium and low ones. Similar moderating effects were found among boys but not girls. CONCLUSION: Caregiver-child interaction plays a vital role in the relationship between SES and child development. Children with low SES households will benefit more in terms of their early development from intervention programs strengthening caregiver-child interaction.

Associations of father absence and limited access to books and toys with early childhood development among children aged 0-6 years in a rural county lifted out of poverty in China.

OBJECTIVES: This study aimed to understand the early development and nurturing care environment of children aged 0-6 years in rural China and to evaluate the sex- and age-specific associations of nurturing care environment with child developmental outcomes. METHODS: A cross-sectional survey involving 2078 children aged 0-6 years was conducted using a stratified cluster sampling strategy. We used face-to-face interviews to collect information on child, family and nurturing care. The Ages & Stages Questionnaires-Chinese version and ASQ: Social-Emotional were applied to assess children's neuro- and social-emotional development, respectively. Lower neurodevelopmental scores indicate an increased risk for neurodevelopmental delay, and higher social-emotional scores are indicative to a risk of social-emotional problems. The multiple linear regression model examined the associations of nurturing care environments with childhood development. RESULTS: Among the investigated children, the average age was (42.9 ± 19.8) months and 55.8% were boys; 67.9% of the children had absent fathers because of labour migration and 54.0% had limited access to books and toys. Overall, boys had a lower total neurodevelopmental score than girls; similar gender patterns were also found in the domains of communication, fine motor, problem-solving and person-social. Concurrent absent fathers and limited access to books and toys were significantly associated with reduced neurodevelopmental scores [ß - 11.44, 95% CI (-18.20, -4.68)] and increased social-emotional developmental scores [ß 5.88, 95%CI (1.35, 10.41)] after controlling for confounding factors. Sex-specific analysis only echoed the results in boys. Additionally, having an absent father and limited access to books and toys was associated with lower neurodevelopmental scores [ß - 14.58, 95%CI (-25.41, -3.75)] in children under 3 years of age and higher social-emotional developmental scores among children aged 3-6 years [ß 10.66, 95%CI (5.09, 16.24)]. CONCLUSIONS: Children, especially boys, with absent fathers due to labour migration have poorer neuro- and social-emotional development. Limited access to books and toys and father absence are linked to the children's developmental delay, especially for those under 3 years of age. Our findings suggest that intervention programs in resource-constrained rural areas are desirable; more importantly, such programs should begin before 3 years of age to achieve a benefit-cost outcome.

Functional chromopeptide nanoarchitectonics: molecular design, self-assembly and biological applications.

Chromoproteins are a class of delicate natural compounds that elegantly complex photosensitive species with proteins and play a central role in important life processes, such as photosynthesis. Inspired by chromoproteins, researchers integrate simple peptides and photosensitive molecular motifs to generate chromopeptides. Compared with chromoproteins, chromopeptides exhibit a relatively simple molecular structure, flexible and adjustable photophysical properties, and a capability of programmable self-assembly. Chromopeptide self-assembly has attracted great attention as the resultant high-level architectures exhibit an ingenious combination of photofunctions and biofunctions. This review systematically summarizes recent advances in chromopeptide nanoarchitectonics with particular focus on the design strategy, assembly mechanism, and structure-function relationship. Among them, the effect of peptide sequences and the variation in photophysical performance are critically emphasized. On this basis, various applications, including biomedicine and artificial photosynthesis, are discussed together with the future prospects of chromopeptide nanoarchitectonics. This review will provide insights into chromopeptide nanoarchitectonics and corresponding materials with precise designs, flexible nanostructures and versatile functions. In addition, knowledge involving chromopeptide nanoarchitectonics may aid in the development of many other kinds of supramolecular biological materials and bioengineering techniques.

Efficient treatment of colon cancer with codelivery of TRAIL and imatinib by liposomes.

To solve the problem of resistance of tumor cells to TRAIL and the inevitable side effects of imatinib during treatment, we successfully prepared a kind of multifunctional liposome that encapsulated imatinib in its internal water phase and inserted TRAIL on its membrane in this study, which named ITLPs. The liposomes appeared uniform spherical and the particle size was approximately 150 nm. ITLPs showed high accumulation in TRAIL-resistance cells and HT-29 tumor-bearing mice model. In vitro cytotoxicity assay results showed that the killing activity of HT-29 cells treated with ITLPs increased by 50% and confirmed that this killing activity was mediated by the apoptosis pathway. Through mechanism studies, it was found that ITLPs arrested up to 32.3% of cells in phase M to exert anti-tumor effects. In vivo anti-tumor study showed that ITLPs achieved 61.8% tumor suppression and little toxicity in the HT-29 tumor-bearing mice model. Overall results demonstrated that codelivery of imatinib and TRAIL via liposomes may be a prospective method in the treatment of the TRAIL-resistance tumor.

Identification of FCER1G as a cyclosporin A plus corticosteroid sensitization gene in female patients with Vogt-Koyanagi-Harada disease.

The resistance development of the combination regimen of corticosteroids (CS) with cyclosporin A (CsA) leads to therapeutic failure of some patients with autoimmune diseases. In the male patients with Vogt-Koyanagi-Harada (VKH) disease, we have identified RPS4Y1 as an important resistance gene of the regimen and a functional mediator of chlorambucil (CLB). However, it remains unclear what is responsible for the resistance in female patients. In the present study, we performed RNA sequencing, tandem mass tag (TMT) proteomics, gain- and loss-of-function assays and rescue assays to screen and validate potential resistant mediators. The results showed that only Fc epsilon receptor Ig (FCER1G) exhibited significantly differential expression in CD4+ T cells among female CsA & CS resistant, sensitive and CLB & CsA & CS treated patients at transcription and protein levels. Inhibition of FCER1G was demonstrated to modulate CD4+ T cell resistance to CsA & CS in female patients. Importantly, the inhibition was mediated by elevated DNA methylation in the promoter region of the FCER1G gene. Moreover, we found that the salvage effect of CLB on CsA & CS resistance was mediated by an increased FCER1G expression via DNA demethylation in female patients. Taken together, the downregulation of FCER1G due to DNA hypermethylation is responsible for the resistance to CsA & CS and CLB reverses this resistance by inducing FCER1G expression via DNA demethylation in female patients. Modulation of FCER1G would be a promising sensitization strategy in female patients with resistance to CsA & CS.